Vascular Neuropathology February 2002

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Vascular Neuropathology February 2002

• Charleen T. Chu, M.D., Ph.D.
• Dept. of Pathology, Division of Neuropathology
• University of Pittsburgh School of Medicine
• Pittsburgh Institute for Neurodegenerative
  Disease
• http//path.upmc.edu/people/faculty/chu.html

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Cerebrovascular Disease

• Ischemic
• Atherosclerosis
• Embolism
• Hypotensive episode
• Hemorrhagic
• Trauma
• Berry aneurysm
• Hypertension, vascular malformations, amyloid
• Superior sagittal sinus thrombosis
• Inflammatory - vasculitis, primary vs. secondary
• Neoplastic - lymphoma, angiosarcoma,
  hemangiopericytoma, hemangioblastoma

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Cerebrovascular Disease

• Third leading cause of death in the US
• Most prevalent neurologic disorder

• Hypoxia, ischemia, infarction
• Intracranial hemorrhage
• Herniation
• Small vessel disease

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Cerebrovascular Disease

• Hypoxia, ischemia, infarction
• Anatomy
• Atherosclerosis and emboli
• Hypotensive episode
• Acute, subacute, chronic infarcts
• Intracranial hemorrhage
• Herniation
• Vasculitis, small vessel disease

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Vascular Supply to the Brain
Modified from Watson 1995 Basic Human
Neuro-anatomy, 5th Edition, p. 103. Little,
Brown Co.
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PCA
ACA
MCA
Modified from Poirier et al.1990 Manual of Basic
Neuropathology, 3rd Edition, Fig. 117, p. 88.
W.B. Saunders
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Anatomic Considerations

• Vascular anatomy
• Circle of Willis and anastomoses (Figs. 109-110 -
  Poirier)
• Internal carotid-middle cerebral artery
• Watershed zone
• Rigid brain case and herniation (Robbins p. 1298)
• Falx
• Tentorium
• Foramen Magnum

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Oil red O stain showing sites of AS
Courtesy of Dr. Julio Martinez
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Plaque rupture
Atheromatous carotid stenosis
Modified from Poirier et al. 1990 Manual of Basic
Neuropathology, 3rd Edition, p. 85. WB Saunders
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Pathology of Cerebral Infarcts

• Distribution
• Fits within vascular territory (atherosclerotic)
• Multiple, grey-white jxn (embolic)
• Vulnerable areas (hypotensive/hypoxic)
• Centered at depths of sulci, sometimes with
  sparing of subpial cortex (in contrast to
  contusion at tips of gyri)
• Age
• Acute
• Subacute
• Remote

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Recent infarct with gyral edema, softening,
discoloration
Courtesy of Dr. Julio Martinez
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Subacute infarcts
Courtesy of Dr. Julio Martinez
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Remote infarcts
Courtesy of Dr. Christine Hulette
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Infarct Age - Gross

• Acute 6-48 h
• Pale, soft, swollen, blurred gray-white jxn
• Subacute 2 d - 3 wks
• 2-10 d Gelatinous, friable, distinct infarct
  boundary Then, gradual removal of tissue
• Remote months-years
• Cystic /- hemosiderin staining
• Secondary degeneration of axon tracts

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Infarct Age - Microscopic

• gt 1 h Neuronal and perineuronal
  vacuolation, Dark neurons
• 4-12 h Red neurons, Pallor (BBB leaky)
• 15-24 h - 5 d Neutrophils
• 2-3 d - wks MØ, myelin phagocytosis
• 1-2 wks Astrocyte vascular prolif.
• mo-yrs Cyst, residual MØ, gliotic wall

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Acute infarcts
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Subacute infarct, HE/LFB stain
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Remote cystic infarct
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Multiple embolic infarcts
Courtesy of Dr. Christine Hulette
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Diffuse hypoxia-ischemia
Vulnerable areas

• Watershed or borderzone
• CA1 region of hippocampus
• Cerebellar Purkinje cells
• Mid- to deeper layers of cortex (pyramidal) -
  laminar necrosis

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Watershed infarcts
Courtesy of Dr. Christine Hulette
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CA2
CA1
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Vulnerability of the Brain

• High consumption of oxygen and glucose
• Dependence on oxidative phosphorylation
• Maintain membrane polarization
• Relatively low levels of antioxidant protection
• Growing evidence for physiologic role for free
  radicals in neurotransmission (NO, O2-)

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Clinical Course

• Stroke
• Acute onset of focal neurologic syndrome due to
  vascular event
• Acute change to pre-existing AS plaque
• Symptoms tend to improve during 1st week after
  stroke
• Believed to reflect acute neuronal death followed
  by resolution of edema

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Lessons from Experimental Systems

• Core - rapid neuron death from lipolysis,
  proteolysis, total bioenergetic failure
• Penumbra - Delayed neuronal death continues for
  days/weeks after insult
• Excitotoxicity
• Spreading dopolarization
• Reactive oxygen and nitrogen species
• Apoptosis
• Inflammation

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Evolution of Ischemic Stroke
Modified from Dirnagl et al. 1999. TINS 22391-397
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Therapies to Salvage Penumbra

• Hypothermia
• NMDA antagonists, block excitotoxicity
• Short window (1-2 h)
• Serious unwanted effects (like off switch of
  tv)
• New selective antagonists (volume control)
• Calcium channel blockers
• SOD mimetics - longer window
• Potential targets for therapies
• iNOS and COX2, anti-apoptotic agents?

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Cerebrovascular Disease

• Hypoxia, ischemia, infarction
• Intracranial hemorrhages
• Epidural
• Subdural
• Subarachnoid
• Intraparenchymal
• Herniation
• Vasculitis, small vessel disease

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Epidural Hemorrhages

• Trauma with skull fx
• Arterial
• Middle meningeal artery
• Can be rapidly expanding gtgt herniation
• Less common in children
• Meningeal vessels not yet deeply embedded in
  grooves of the cranium
• Dense dark-red clot adherent to dura
• Can be venous from infratentorial base of skull
  fxs with laceration of dural sinus

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Subdural Hemorrhage

• Bridging veins
• Early (Acute and subacute)
• Trauma, associated with brain contusion
• Mixture of blood and CSF - may not clot
• Chronic
• Mainly in elderly, may not recall trauma
• Slow development, may distort brain
• Fibrous organization and rebleeding common -
  sepia/yellow staining

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Subdural membrane with rebleeding
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SAH
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Subarachnoid Hemorrhage

• Saccular (Berry) Aneurysms
• 1.8 of autopsies
• Congenital defect in media at branch point
• 90 in anterior circulation
• Repetitive bleeding gt loculations gt rupture into
  adjacent parenchymal
• Plaques, calcifications, thrombi
• Associated with polycystic kidney disease

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MCA
ACA
ICA
Ruptured Aneurysms
Modified from Poirier et al.1990 Manual of Basic
Neuropathology, 3rd Edition, p. 73. W.B.
Saunders Co.
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Intraparenchymal extension from ruptured anterior
communicating artery aneurysm
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Intraparenchymal Hemorrhage

• 15 mortality
• Arterial hypertension - 80 of cases
• Vascular malformations
• Amyloid angiopathy
• Neoplasms

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Other intracranial aneurysms

• Seldom present as SAH
• Fusifirm atherosclerotic aneurysms
• Basilar artery
• Compression of adjacent structures
• Infectious and post-traumatic
• Mycotic, traumatic, dissecting
• Usually involve anterior circulation

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Arterial dissection

• Young adults - IC, MCA, vertebral, basilar
• Hyperextension injury - may be trivial
• Spontaneous dissection
• Arteritis, AS, HTN, birth control pill, Marfans,
  cystic medial necrosis, fibromuscular dysplasia,
  Ehlers-Danlos
• Focal absence, splitting, fraying of internal
  elastic membrane
• 33 no identifiable pathology

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Intraparenchymal Hemorrhage

• Massive hemorrhage of the basal ganglia, WM,
  pons, cerebellum gtgt Hypertension
• Superficial/lobar gtgt contusion, amyloid, AVM
• Parasagittal gtgt venous thrombosis, SSS
• Petechial gtgt blood dyscrasias, fat emboli
• Multiple hemorrhaghic infarcts gtgt emboli (tumor,
  infectious, cardiac)
• Neoplasms can present as hemorrhage

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Hypertensive hemorrhage
Courtesy of Dr. Julio Martinez
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Hypertensive hemorrhage
Courtesy of Dr. Julio Martinez
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Surgical Pathology Hemorrhages

• Usual dx - clotted blood
• May see erythrophagocytosis, fibrovascular
  organization, subdural membrane gt then can call
  organizing hemorrhage/hematoma
• Look for brain tissue and note in report
• If present, look for underlying cause
• Congophilic angiopathy (b-APP, cystatin C)
• Tumor
• AVM

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Congophilic angiopathy in resected hematoma
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CNS Vascular Malformations

• Arteriovenous malformation (AVM)
• Cavernous hemangioma
• Capillary telangiectasia - pons
• Venous angioma (varices)

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Arteriovenous malformation

• Medusa-like lesions with potential for rupture
• Most over hemispheric surface of MCA
• Multiple lesions occasionally seen with
  Rendo-Osler-Weber disease or Wyburn-Mason
  syndrome
• Sx seizures, focal deficits, increased ICP,
  catastrophic hemorrhage

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AVM - Pathology

• Vessels vary in caliber
• Core may exclude brain parenchyma, but feeding
  and draining vessels interdigitate with
  intervening brain
• Presence of abnormal arteries possessing internal
  elastic lamina is diagnostic
• Arterialized veins from the high pressure
• Evidence of prior hemorrhage

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Arteriovenous malformation

• In children, deep AVMs draining into the great
  vein of Galen can cause cardiac decompensation
  from shunting

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Cavernous Malformations

• Compact spherical calcified mass
• Most often affect subcortical areas, but also
  hindbrain
• Multiple lesions frequent
• Recently recognized that it can be transmitted as
  an autosomal dominant trait
• Typically present with seizures. Hemorrhages
  common, but usually small

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Cavernous Malformations

• Honeycomb of compact vessels, often collagenized
• No muscle or elastic lamina
• Closely packed, no intervening brain
• Surrounding brain shows extensive hemosiderin and
  iron laden macrophages/astrocytes - dark MR signal

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Venous Infarction

• Hemorrhagic lesions involving parasagittal
  meninges, cortex, WM
• Superior sagittal sinus thrombosis
• Centrum ovale and overlying cortex, meninges,
  usually symmetric
• Great vein of Galen
• Periventricular and thalamic regions

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SSS Thrombosis
Courtesy of Dr. Julio Martinez
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Brain tumors presenting with hemorrhage

• Classically associated with oligodendroglioma,
  choriocarcinoma, metastatic melanoma
• However, any glioma can present with hemorrhage
• Recent examples include GBM, anaplastic
  ependymoma
• Post-operative hematoma from incompletely excised
  tumors - clinical history often not given

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Cerebrovascular Disease

• Hypoxia, ischemia, infarction
• Intracranial hemorrhages
• Herniation
• Symptoms
• Anatomic basis
• Vasculitis, small vessel disease

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Herniation

• Rigid skull, tough inelastic dura
• Brain, CSF, blood

• Symptoms of increased pressure
• Headache
• Papilledema - precedes herniation

• Symptoms of transtentorial herniation
• Remember anatomic basis

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Herniation

• Symptoms of transtentorial herniation
• Pupillary dilation, lateral deviation
• Cortical blindness
• Coma
• Hemiparesis, usually contralateral, but can be
  ipsilateral (false localizing sign)
• Hydrocephalus, Duret hemorrhages of pons

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How do each of these colored structures relate to
SSx of herniation listed on previous slide?
Modified from Watson 1995 Basic Human
Neuro-anatomy, 5th Edition Little, Brown Co.
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Bilateral uncal herniation with midbrain
compression, secondary occipital infarcts
Courtesy of Dr. Christine Hulette
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Cerebrovascular Disease

• Hypoxia, ischemia, infarction
• Intracranial hemorrhages
• Herniation
• Vasculitis, small vessel disease
• Temporal arteritis
• Microvascular diseases
• HTN, amyloid angiopathy, primary angiitis of the
  CNS
• Petechial hemorrhages

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Primary vasculitides

• Takayasus - aorta, carotid, subclavian
• Media, destruction of elastic lamellae
• Temporal arteritis - extracranial aa
• Primary angiitis of the CNS - small meningeal aa
  and penetrating arterioles

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Temporal (giant cell) arteritis

• gt55 yrs old with headache and blindness
• Predominantly affects extracranial arteries of
  the head
• High ESR
• Good, rapid response to corticosteroids
• Focal histopathological changes
• Need to sample thoroughly

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Temporal arteritis - histology

• It is a transmural process, focused on media and
  adventitia
• Nonspecific intimal proliferation, /- lymphs
• Inner media
• Multinucleated giant cells, epithelioid
  histiocytes
• Frayed internal elastic lamina
• Adventitia
• Epithelioid histiocytes, lymphs
• Chronic, healed - transmural fibrosis

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Microvascular diseases

• Disease of arterioles and other small parenchymal
  vessels
• Radiologic entity - white matter pallor
• Multiple divergent pathological causes
• Degenerative - HTN, amyloid angiopathy
• Inflammatory - vasculitis ( J Neuropath Exp
  Neurol 57 30-38)
• Petechial hemorrhages
• Embolic - cholesterol, fat
• Disruptions of coagulation - TTP, lupus

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Hypertensive Angiopathy

• Penetrating arteries, 75-400 ?m
• Vascular wall thickening
• Fibrinoid change or necrosis
• Segmental weakening and dilatation
• Charcot-Bouchard aneurysms
• Lacunes
• lt15 mm infarcts, /- associated hemorrhage

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arteriolosclerosis
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Primary angiitis of the CNS

• Noninfectious granulomatous angiitis or isolated
  angiitis of the CNS
• Untreated - almost universally fatal
• Combination steroid and cytoxan
• ESR variable and not diagnostically useful, CSF
  resembles chronic meningitis
• Transmural granulomatous or lymphocytic
  inflammation, esp. intima, media
• Rule out infectious vasculitides

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PACNS - DDx
J Neuropath Exp Neurol 57 30-38, 1998.

• Clinical mimics - hypertension, AD, amyloid
  angiopathy, glioma, antiphospholipid syndromes,
  moyamoya, fibromuscular dysplasia, cardiac myxoma
  embolism)

• Pathologic DDx - viral infection, Hodkins,
  lymphomatoid granulomatosis, systemic rheumatic
  disorders ( SLE, sarcoid), drug hypersensitivity

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PACNS
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Vasculitis secondary to arboviral infection, Am J
Surg Pathol, 23 1217-1226
Congophilic angiopathy
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Petechial hemorrhages
Courtesy of Dr. Julio Martinez
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TTP
Courtesy of Dr. Julio Martinez
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Fat embolus, Oil red O
Courtesy of Dr. Julio Martinez
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Self quiz (see next slide)

• Which two panels show pathology related to a
  common etiology (cause)?
• What panel results from trauma, what is anatomic
  space occupied by the lesion, and what vessel is
  commonly involved?
• Which panel reflects differential neuronal
  susceptibility to injury?
• Which panel reflects a chronic process?

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Self quiz (answers)

• B shows hypertensive hemorrhage originating in BG
  and C shows lacunar infarcts in the BG, also
  related to hypertension.
• The subdural hemorrhage in A results from trauma,
  sometimes so mild it is not remembered, and
  involves bridging veins
• D shows acute neuronal injury (red neurons) in
  the region of the hippocampus susceptible to
  hypotensive-hypoperfusion injury?
• C shows remote cerebellar infarct

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Recommended Reading

• Manual of Basic Neuropathology by Poirier et al.
• Pp. 52-56, 58-61, Chapter 4.
• Robbins Pathologic Basis of Disease by Cotran,
  Kumar, and Collins 6th Ed.
• Pertinent sections of Chapter 30 (CNS).
• Greenfields Neuropathology text - a must for all
  NP fellows